1. Field of the Invention
This invention relates to new anthracycline antibiotics, to methods for their use as antimicrobial and antitumor agents, to pharmaceutical compositions containing them and to methods for the preparation and recovery of said new compounds as well as certain previously reported anthracycline antibiotics.
2. Description of the Prior Art
Various types of anthracycline glycosides have been found in the cultured broth of microorganisms and described in the literature. Among them, daunomycin and adriamycin have already been applied clinically for human cancers, and aclacinomycin A, carminomycin and rubidazone are under clinical trials with keen interest in the field of cancer chemotherapy.
As a result of screening cultures of Streptomyces for metabolites having antitumor activity, the present inventors have discovered new compounds and after purification and characterization based on their physico-chemical properties, they have confirmed that the antibiotics now named MA 144-G1, -G2, -L, -N1, -S1, -U1 and -Y are new anthracycline glycosides which have potent antitumor activity and low toxicity in mammals. Additionally, they have established processes and methods for the preparation and purification of these new antibiotics as well as for the antibiotics named MA 144-S2 and -U2 which have been determined to be identical with the previously reported anthracycline glycosides, marcellomycin and musettamycin (see U.S. Pat. No. 4,039,736).
Preparation of adriamycin by fermentation of S. peuceticus var. caesius is disclosed in U.S. Pat. No. 3,590,028. Chemical conversion of daunomycin to adriamycin is taught in U.S. Pat. No. 3,803,124.
Daunomycin (produced by fermentation of S. peuceticus in U.K. Pat. No. 1,003,383) may be the same as Rhone-Poulenc's 13,057 R.P. (formerly rubidomycin and now daunoribicin; see U.K. Pat. Nos. 985,598, 1,188,262 and 1,241,750 and U.S. Pat. No. 3,616,242) and is probably identical to Ciba's danubomycin disclosed in U.S. Pat. No. 3,092,550 and U.K. Pat. No. 901,830. See also U.S. Pat. No. 3,686,163 on dihydrodaunomycin.
Anthracycline antibiotics having the aklavinone aglycone moiety are disclosed as follows:
(a) aclacinomycin A and B in U.S. Pat. No. 3,988,315 and by Oki et al. in J. Antibiotics 28:830 (1975). PA1 (b) aklavin in J. Bacteriol. 72:90 (1956). PA1 (c) musettamycin and marcellomycin from bohemic acid complex in J. Antibiotics 30:525 (1977) and in U.S. Pat. No. 4,039,736. PA1 (d) pyrromycin in Chem. Ber. 92:1904 (1959). PA1 (e) cinerubin A and B in U.K. Pat. No. 846,130 (see also U.S. Pat. No. 3,864,480 and Keller-Schierlein et al. Antimicrobial Agents and Chemotherapy, page 68 (1970)). PA1 (f) nogalamycin in J. Amer. Chem. Soc. 99:542 (1977). PA1 (g) steffimycin in J. Antibiotics 27:805, 809 (1974). PA1 (h) carminomycin in J. Antibiotics 27:254 (1974), in U.K. Pat. No. 1,426,637 and in J. Amer. Chem. Soc. 97:5955 (1975). PA1 (i) trypanomycin in Antimicrobial Agents and Chemotherapy 1:385 (1972). PA1 (j) requinomycin in J. Antibiotics 25:393 (1972). PA1 (k) galirubin A and B in Naturwiss. 52:539 (1965) and Chem. Abst. 67:90573z (1967). PA1 Aclacinomycin A as substrate (0.4 .mu.mole/ml.): 0.25 ml. PA1 0.2 M citrate buffer (pH 5.5): 0.25 ml. PA1 Enzyme solution: 0.50 ml. PA1 Molecular weight: 72,000 PA1 Isoelectric point: pH 5.9 PA1 Optimal pH: 5.5 PA1 pH stability: 5.0 to 8.0 PA1 Thermal stability: under 50.degree. C. (neutral pH) PA1 Reaction condition: Oxygen dependent PA1 Km: 0.125 mM PA1 Inhibitors: Fe.sup.++, SO.sub.3.sup.--, S.sub.2 O.sub.4.sup.--, S.sub.2 O.sub.5.sup.--, NaN.sub.3, Ascorbic acid, NADPH and hydrogen donors PA1 Potato starch: 2% w/v PA1 Glucose: 2 PA1 "Meat" (Trademark of Soybean Powder): 2.5 PA1 KH.sub.2 PO.sub.4 : 0.1 PA1 K.sub.2 HPO.sub.4 : 0.1 PA1 MgSO.sub.4.7H.sub.2 O: 0.1 PA1 NaCl: 0.3 PA1 MnCl.sub.2.4H.sub.2 O: 0.0005 PA1 FeSO.sub.4.7H.sub.2 O: 0.0005 PA1 Silicone: 0.005 (pH 7.2)
Anthracycline antibiotics having the .epsilon.-pyrromycinone aglycone moiety are described in the literature as follows:
Other anthracycline antibiotics having an aglycone different from aklavinone and .epsilon.-pyrromycinone are described in the following literature:
For further illustrative and summary disclosures of anthracycline antibiotics, see Index of Antibiotics from Actinomycetes, Hamao Umezawa, Editor-in-Chief, University Park Press, State College, Pennsylvania, U.S.A. (1967) as follows:
______________________________________ Antibiotic Page Number ______________________________________ Aklavin 111 Cinerubin A 220 Cinerubin B 221 Danubomycin 242 Daunomycin 243 Pyrromycin 524 Rhodomycin A, B 561 Rubidomycin 574 ______________________________________
The textbook Antibiotics, Vol. 1, Mechanism of Action, edited by David Gottlieb and Paul D. Shaw, Springer-Verlag New York, Inc., N.Y., N.Y. (1967) at pages 190-210 contains a review by A. DiMarco entitled Daunomycin and Related Antibiotics. Information Bulletin, No. 10, International Center of Information of Antibiotics, in collaboration with WHO, December 1972, Belgium, reviews anthracyclines and their derivatives.